Project Summary/Abstract The sense of taste is a major regulator of eating behavior; taste informs the body of diet composition, and helps us select beneficial foods that ensure daily needs and avoid harmful compounds. Taste dysfunction has dramatic effects on human health. For instance, patients undergoing irradiation treatment for head and neck cancer suffer from taste disruption which deeply affects their quality of life, i.e. causing psychological distress, malnutrition and weight loss. Although up to 90% of these patients suffer from taste disturbance, the mechanisms responsible are poorly understood. One likely cause is that radiation affects taste bud cell renewal. Taste stimuli, including sweet, bitter, sour, salt and umami, are detected by oral taste buds found mostly on the tongue. Taste bud cells are continuously renewed from taste bud stem cells or progenitors to maintain the integrity and function of the taste buds throughout adult life. Our lab has shown in mice that a single dose of irradiation to the head and neck greatly reduces proliferation of taste cell progenitors and their production of differentiated taste cells. This impact is transient and taste bud homeostasis recovers within 10 days after irradiation. However, this simple model of single dosing does not replicate radiotherapy for cancer patients who are given a low fractionated dose daily for up to 7 weeks. For these patients, taste perception is dramatically reduced during treatment and remains significantly altered in the months, and often years, following treatment. Therefore, in Aim 1 I will characterize the cellular mechanisms underlying the long term impact of repeated radiation on taste cell homeostasis. Additionally, it is unknown how irradiation disrupts taste cell renewal at the molecular level. I have shown that Wnt/?-catenin signaling controls proliferation of taste progenitors and differentiation of taste bud cells (Gaillard et al., PLOS Genetics, 2015), and is required for taste cell renewal as loss of pathway function leads to a progressive reduction of progenitor proliferation and differentiated taste bud cells (Gaillard et al. 2016 Chem Senses, In Press; Gaillard et al., in prep.). I present new pilot data here that Wnt/?-catenin signaling is upregulated following single dose irradiation and that the timing of this increase correlates with the initiation of proliferation that underlies recovery of taste homeostasis after irradiation. This finding is particularly important because it suggests that activation of Wnt signaling could be used as an approach to mitigate injury to the taste system. Thus in Aim 2, I will characterize Wnt/?-catenin signaling following fractionated irradiation and explore if transient activation of the Wnt effector, ?-catenin, rescues taste progenitor function and taste bud homeostasis.